WO1987005016A1 - Pyridazinone derivatives or salts thereof - Google Patents

Pyridazinone derivatives or salts thereof Download PDF

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Publication number
WO1987005016A1
WO1987005016A1 PCT/JP1986/000083 JP8600083W WO8705016A1 WO 1987005016 A1 WO1987005016 A1 WO 1987005016A1 JP 8600083 W JP8600083 W JP 8600083W WO 8705016 A1 WO8705016 A1 WO 8705016A1
Authority
WO
WIPO (PCT)
Prior art keywords
salts
acid
add
present
pyridazinone
Prior art date
Application number
PCT/JP1986/000083
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Hiromi Okushima
Akihiro Narimatsu
Makio Kobayashi
Rikizo Furuya
Yoshimi Kitada
Original Assignee
Mitsubishi Chemical Industries Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP59167336A priority Critical patent/JPS6144873A/ja
Application filed by Mitsubishi Chemical Industries Limited filed Critical Mitsubishi Chemical Industries Limited
Priority to AT86901500T priority patent/ATE71089T1/de
Priority to EP86901500A priority patent/EP0258435B1/en
Priority to HU861996A priority patent/HU197897B/hu
Priority to DE8686901500Q priority patent/DE3683295D1/de
Priority to PCT/JP1986/000083 priority patent/WO1987005016A1/ja
Priority to US07/026,758 priority patent/US4822797A/en
Publication of WO1987005016A1 publication Critical patent/WO1987005016A1/ja

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms

Definitions

  • the present invention is useful as a cardiotonic agent]), a novel pyridazinone derivative or a salt thereof having a vasodilatory effect and an antihypertensive effect.
  • Cardiotonic drugs have the effect of directly acting on the heart to increase its contractile force, and various drugs have conventionally been used to treat heart failure.
  • cardiotonic drugs have the disadvantage that the safety margin is extremely narrow and arrhythmia is caused by i9 or its cardiotonic effect is transient and unsuitable for oral administration There are many things.
  • the present inventors have conducted a search for a compound having high activity as a cardiotonic agent and capable of sufficiently exhibiting the sustainability of the effect, and have reached the present invention. Disclosure of the invention
  • the gist of the present invention is the following general formula (I):
  • R 2 and R 3 represent a hydrogen atom, a hydroxyl group or an alkoxy group having a carbon number of less than or equal to (methoxy, ethoxy, propoxy, butyl) ⁇ , ⁇ , and ⁇ and ⁇ ⁇ together represent 1 0— GH 2 — 0— or 1 0—CE.
  • R 4 represents an alkyl group (preferably an alkyl group having not more than carbon atoms), and n represents 0 to 2 -CH 2 -0-. Represents an integer, and the dotted line represents a single bond or a double bond.)
  • pyridazinone derivative or a salt thereof In the pyridazinone derivative or a salt thereof.
  • the pyridazinone derivative in the method of the present invention can be synthesized, for example, by the following route.
  • the compound of the above general formula (I) can be produced by the usual amide bond formation reaction between carboxylic acid (E) or a derivative thereof and amide ( ⁇ 1). .
  • the mixed acid-hydrate method that is, the reaction of carboxylic acid ( ⁇ ) with alkyl carboxylic acid to give a mixed acid anhydride, m)
  • the (carbo) carbodimid method that is, carboxylic acid ( ⁇ ) and amide (m) are introduced into the mouth
  • a method of condensation in the presence of a imide such as a 7k complex ij, a carboxylic acid halide method, an active ester method, etc. may be mentioned, but the mixed anhydride method is preferred.
  • Mixed acid anhydrides include basic compounds (triethylamine. Pyridin, diazabicyclo decene (DB-II)), organic bases, and potassium carbonate. In the presence of sodium carbonate or any inorganic base), carboxylic acid ( ⁇ ) and alkylhalocarboxylic acid can be treated with tetrahydrofuran and dioxan. , Toluene, chlorophosolem, gfe acidhole, dimethylene noiromit,,,
  • the reaction temperature ranges from about 1 to about 2 ° C, and the reaction time ranges from about 1 minute to about 1 minute.
  • the resulting mixed acid anhydride can be reacted with the amide ( ⁇ 1) without isolation.
  • the reaction with amimin is one. 2 ⁇ ⁇ . At C, it is performed for about i minutes to hours.
  • Carbonic acid (E) can be obtained from the Journal of Medicinal Chemistry (J. Med. Chem.) / Volume 7, 2 ⁇ / — 2 ⁇ page (/? 7). Year).
  • Amin (1) is a well-known piperazine derivative.
  • Examples of the pyridazinone derivative of the present invention obtained by the above-mentioned method include the following compounds.
  • the compounds of the present invention include those in which the substituent R 4 is a methyl group.
  • Compounds such as R 4 ethyl, propinole-butynole, and pentinole groups are also included in the compounds of the present invention. Be done
  • salts of the above compounds are included in the scope of the present invention.
  • the salts include salts of mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, and nitric acid, and salts of organic acids such as lactic acid, acetic acid, and oxalic acid. All of these compounds are useful as cardiotonic agents, and also have vasodilatory and barolytic effects.
  • the compound according to the present invention when used as a cardiotonic agent, the compound can be administered orally or parenterally. ⁇
  • the form provided may be for oral administration, such as powders, granules, tablets, dragees, pills, capsules, solutions, etc., for non-oral administration.
  • oral administration such as powders, granules, tablets, dragees, pills, capsules, solutions, etc.
  • the amount of the compound of the present invention to be administered as a cardiotonic drug depends on age, gender, body weight, sensitivity difference, administration method, time of administration, interval, degree of medical condition, physical condition, properties of pharmaceutical preparation, preparation, kind, kind of active ingredient: ⁇ Consider a doctor and ask your doctor! ) It is determined.
  • a dose of about 0.1 to about 10% of body weight / day / day is selected, but it is needless to say that the dose is limited to this.
  • New paper Hereafter, according to the examples! ) The present invention will be described in more detail, but the present invention is not limited to the following examples as long as the gist is not exceeded.
  • the silica gel to which the obtained target substance was adsorbed was placed on a column filled with a 30 f silica gel, and a chloroform / methanol solvent was used. (Up to 1/0 //).
  • the fraction containing the target substance is evaporated, and the obtained target substance is N, N-dimethylformamide? ⁇ ⁇ ⁇ ⁇ I 0 0 0 N N N N N N N N N N N N / N
  • add 50 mi of xanthine ether and w-n-hexane add 50 mi of xane, precipitate the precipitate B, filter it, dry it, and dry it to obtain the desired product.
  • 1/1 / Pilazinolone force / Nil] Feninole] 1 ⁇ , J "-Ji-Hydr-J-Metinor-J ( 2H) 1 pyridazinone hydrochloride
  • the obtained gel with the target substance adsorbed thereon is placed on a column filled with 40 ⁇ of the gel with a gel, and a black hole solvent / metano mono-solvent is used. (Cross mouth home alone / up to 0 //:
  • New paper was used for column chromatography purification.
  • the fraction containing the target substance is evaporated, and the obtained target substance is N, LT-dimethylmethylformamide? ⁇ And ethanol
  • the pharmacology test method is described below.
  • CO cardiac output
  • the catheter destination Ma Roh menu COMPUTER to the left ventricle, to measure the left ventricular pressure, it'll change rate of the electrically left ventricular pressure the (d P Z) required
  • New paper I did. A strain gauge on the right ventricle wall! ) The right ventricular muscle contraction force (Cont) was measured. Systemic blood pressure was measured from the left femoral artery. Heart rate is ECG (Lead I)]? The compound dissolved in the solvent was intravenously administered to the left femoral vein.
  • the pyridazinone derivative or a salt thereof of the present invention is useful as a cardiotonic agent, and has a vasodilatory effect and a hypotensive effect.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP1986/000083 1984-08-10 1986-02-21 Pyridazinone derivatives or salts thereof WO1987005016A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP59167336A JPS6144873A (ja) 1984-08-10 1984-08-10 ピリダジノン誘導体またはその塩類
AT86901500T ATE71089T1 (de) 1984-08-10 1986-02-21 Pyridazinon-abkoemmlinge und deren salze.
EP86901500A EP0258435B1 (en) 1984-08-10 1986-02-21 Pyridazinone derivatives or salts thereof
HU861996A HU197897B (en) 1984-08-10 1986-02-21 Process for producing pyridazinone derivatives, the salts thereof and pharmaceutical compositions containing the same
DE8686901500Q DE3683295D1 (de) 1984-08-10 1986-02-21 Pyridazinon-abkoemmlinge und deren salze.
PCT/JP1986/000083 WO1987005016A1 (en) 1984-08-10 1986-02-21 Pyridazinone derivatives or salts thereof
US07/026,758 US4822797A (en) 1984-08-10 1986-02-21 Piperazinyl carbonyl phenyl pyridazinone derivatives useful as cardiotonics

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP59167336A JPS6144873A (ja) 1984-08-10 1984-08-10 ピリダジノン誘導体またはその塩類
PCT/JP1986/000083 WO1987005016A1 (en) 1984-08-10 1986-02-21 Pyridazinone derivatives or salts thereof

Publications (1)

Publication Number Publication Date
WO1987005016A1 true WO1987005016A1 (en) 1987-08-27

Family

ID=55359271

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1986/000083 WO1987005016A1 (en) 1984-08-10 1986-02-21 Pyridazinone derivatives or salts thereof

Country Status (7)

Country Link
US (1) US4822797A (enrdf_load_stackoverflow)
EP (1) EP0258435B1 (enrdf_load_stackoverflow)
JP (1) JPS6144873A (enrdf_load_stackoverflow)
AT (1) ATE71089T1 (enrdf_load_stackoverflow)
DE (1) DE3683295D1 (enrdf_load_stackoverflow)
HU (1) HU197897B (enrdf_load_stackoverflow)
WO (1) WO1987005016A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0339208A1 (de) * 1988-04-26 1989-11-02 HEUMANN PHARMA GMBH & CO 6-Oxo-pyridazinderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3902316A1 (de) * 1989-01-26 1990-08-02 Lentia Gmbh Neue piperazinylalkyl-3(2h)-pyridazinone, verfahren zu ihrer herstellung und ihre verwendung als blutdrucksenkende mittel
US6432956B1 (en) * 1990-02-12 2002-08-13 William C. Dement Method for treatment of sleep apneas
DE69215439T2 (de) * 1991-06-25 1997-05-22 Eastman Kodak Co Photographisches Element, enthaltend eine Spannung absorbierende, schützende Schicht
TW309520B (enrdf_load_stackoverflow) * 1994-04-26 1997-07-01 Mitsubishi Chem Corp
DE19929782A1 (de) * 1999-06-29 2001-01-04 Bayer Ag 6-Carboxyphenyldihydropyridazinon-Derivate und ihre Verwendung
CA2450018A1 (en) * 2001-04-27 2002-11-07 Mitsubishi Pharma Corporation Crystal of 6-[4-(4-pyridylamino)phenyl]-4, 5-dihydro-3(2h)-pyridazinone hydrochloride trihydrate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60197660A (ja) * 1984-03-21 1985-10-07 Mitsubishi Chem Ind Ltd ピリダジノン誘導体またはその塩類

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0107735B1 (en) * 1981-10-20 1988-10-19 Mitsui Toatsu Kagaku Kabushiki Kaisha Novel pyridazinone derivatives
DE3302021A1 (de) * 1983-01-22 1984-07-26 Basf Ag, 6700 Ludwigshafen 6-aryl-4,5-dihydro-3(2h)-pyridazinone, ihre herstellung und verwendung
US4631279A (en) * 1984-10-15 1986-12-23 Eli Lilly And Company 6-(pyridinylphenyl)dihydropyridazinones as inotropic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60197660A (ja) * 1984-03-21 1985-10-07 Mitsubishi Chem Ind Ltd ピリダジノン誘導体またはその塩類

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0339208A1 (de) * 1988-04-26 1989-11-02 HEUMANN PHARMA GMBH & CO 6-Oxo-pyridazinderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
US4968683A (en) * 1988-04-26 1990-11-06 Heumann Pharma Gmbh & Co. 6-oxo-pyridazine derivatives, a process for their preparation and medicaments containing these compounds

Also Published As

Publication number Publication date
EP0258435B1 (en) 1992-01-02
US4822797A (en) 1989-04-18
ATE71089T1 (de) 1992-01-15
EP0258435A4 (en) 1989-01-18
HUT45994A (en) 1988-09-28
JPH0545585B2 (enrdf_load_stackoverflow) 1993-07-09
JPS6144873A (ja) 1986-03-04
DE3683295D1 (de) 1992-02-13
HU197897B (en) 1989-06-28
EP0258435A1 (en) 1988-03-09

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